DESCRIPTION: Spinal cord injury (SCI) often damages, not only white matter axon tracts that transmits signals to and from the brain, but also the central gray matter, causing segmental loss of interneurons and motor neurons. Transplantation of neural stem cells has the potential to replace lost neurons and glia. These transplanted neurons can form functional relays between spinal segments disconnected by the injury. This neuronal replacement strategy is particularly appealing for chronic SCI, which has a relatively stable lesion site and thus do not respond to neuroprotection treatments that can potentially benefit acute SCI. Our preliminary data provide evidence that human neural stem cells can be transplanted into the chronic rat contusion, survive, differentiate into neurons, and extend axonal processes into host spinal cord. The proposed studies will determine whether these human stem cells derived from human embryonic stem cells can integrate into rat spinal cord circuitry and support functional relays resulting in behavioral recovery. Furthermore, we will explore how rehabilitation can refine theses relay to enhance behavioral recovery. This work is highly innovative and clinically oriented: 1) We will utilize a contusion type injury that is most applicable to human SCI. 2) We will employ neural stem cells derived from clinically compliant human embryonic stem cells that will ease clinical translation. 3) We will combine neural stem cell grafting with rehabilitation tht is currently the standard of care for chronic SCI.